2.1. Introduction
Melanoma is the seventh most common malignancy in the U.S. The American Cancer Society estimates that approximately 130,000 new cases of melanoma, including 76,250 invasive and 55,560 non-invasive melanomas, will be diagnosed in 2012 and about 9200 people will die of melanoma (Siegel et al., 2012, CA Cancer J Clin. 62(1):10-29). If a melanoma is identified and removed before metastasis has occurred, there is a relatively high rate of cure.
Once metastasis has taken place, there are few current therapies that can contain or reverse the adverse effects of malignant melanoma. It is a deadly disease with few systemic treatment options compared to many other cancers. Currently patients diagnosed with an advanced stage of the disease have less than a 15% 5-year survival rate. New inhibitors of BRAFV600E, such as Zelboraf (Bollag 2010) and the CTLA-4 inhibitor Yervoy, have recently been found to influence melanoma survival in clinical trials. Bollag et al., 2010 Nature 467(7315):596-9; Robert et al., 2011 N Engl J Med 364(26):2517-26. However, both of these agents are either limited to a small subset of patients or have only short-term clinical benefits due to the rapid development of resistance (Chapman et al., 2011 N Engl J Med 364(26): 2507-16; Eggermont and Robert, 2011 Eur J Cancer 47: 2150-2156; Hodi et al., 2010 N Engl J Med 363(8): p. 711-23). Clearly new therapeutics are needed to enable the effective clinical management of malignant melanoma.
2.2. Companion Diagnostics
Many cancer drugs are approved for use with a companion diagnostic. For example, trastuzumab (Herceptin®) is approved for breast cancer over expressing ERB-B2 and cetuximab (Erbitux®) for patients with wild-type KRAS. Amado et al., 2008, J Clin Oncol 26 (10): 1626-1634; Allegra et al., 2009 J Clin Oncol 27 2091-2096. Another cancer drug approved for use with a diagnostic is crizotinib (Xalkori®) approved for non-small cell lung cancer (NSCLC) with a fluorescent in situ hybridization (FISH) test for ALK rearrangements (Vysis LSI ALK Dual Color, Break Apart Rearrangement Probe; Abbott Molecular, Abbott Park, Ill.). Shah et al., 2011 Lancet Oncol 12 1004-1012; Shaw et al., 2009 J Clin Oncol 27 4247-4253. Vemurafenib (Zelboraf®) is approved for melanoma in patients with BRAF V600E mutation (Cobas 4800 BRAF V600 Mutation Test, Roche Molecular Diagnostics, Pleasanton, Calif.). Chapman et al., 2011.
Our earlier work investigating DNA methylation during the progression of melanoma showed that the promoter of ITK was demethylated in primary melanomas and could lead to aberrantly expressed ITK protein in those lesions. Conway et al., 2011 Pigment Cell Melanoma Res. 24(2):352-60. ITK (IL-2 inducible T-cell kinase) is a member of the TEC family of tyrosine kinases that have been implicated in T cell activation, development, and differentiation. ITK has a restricted expression profile, normally found only in mast cells and T lymphocytes, and has been shown to signal in association with the PI3 kinase pathway following activation by the TCR (T Cell Receptor) complex. ITK plays an important role in T cell signaling and the production of various pro-inflammatory cytokines such as IL-2, IL-4, IL-5, IL-10 and IL-13. Drugs targeting ITK are under development for the treatment of diseases related to inflammation disorders such as psoriasis and allergic asthma or for T cell leukemia or lymphoma.